This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. CD36 is a broadly expressed glycoprotein acting as a facilitator of fatty acid uptake, a signaling molecule and a receptor for a wide range of ligands, including apoptotic cells, modified forms of low density lipoprotein, thrombospondins, fibrillar [unreadable]-amyloid and components of Gram positive bacterial walls. CD36 is expressed on macrophages, dendritic and endothelial cells, and in tissues including muscle, heart and fat. Its omnipresence suggests its diverse roles. Indeed, it is a multifunctional receptor involved in both homeostatic and pathological conditions. Despite a rapid increase in our knowledge of CD36 functions its structure is still unknown and the mechanistic aspects of this protein remains elusive. These two aspects are interrelated and calls for a comprehensive function and structure studies of this important membrane protein. CD36 is a ditopic membrane protein. The human CD36 gene is currently reported to extend about 28 kb on chromosome 7q and encodes a predicted protein of 471 amino acids with a molecular weight of 52,922 Da. Human CD36 has a large extracellular domain characterized by 10 N-linked glycosylation sites, and as a result the actual molecular weight varies from 80-90 kDa. We are interested in the role of CD36 in cardiovascular diseases and especially in the pathogenesis of atherosclerosis, the main cause of heart attack. CD36 and scavenger receptor A (SRA) are the principal macrophage receptors responsible for the uptake of modified forms of LDL, leading to cholesterol accumulation and macrophage foam cell formation, the cellular hallmark of atherosclerosis. Using the apoE KO model of atherosclerosis, our lab has made significant contribution to the relevance of CD36 to the pathogenesis of cardiovascular disease. CD36/apoE double KO mice of both genders have significantly less aortic lesion area in the after 12 weeks of Western diet feeding. We have also shown that the absence of CD36 in hematopoietic cells accounted for the protection observed in the apoE KO model. Parallel experiments of long term Western diet feeding of mice indicated that CD36 continued to play a role in lesion development as a consequence of continued recruitment of macrophages and development of foam cells. To block this adverse effect of CD36 we need to look for some ligands which could serve as inhibitors to prevent the formation of macrophage foam cells. This is where a better understanding of CD36 structure is critical. After a routine high throughput screening we have found some small molecule inhibitors with high affinity to recombinant functional extracellular binding domain of human CD36. The structure determination of the complex of the ligands and CD36 will shed light on the interaction between the protein and the inhibitor. This will provide us with useful information for the design of specific therapeutic drugs to combat atherosclerosis.